Hepatocellular carcinoma (HCC) is an aggressive malignancy that has a survival rate of 14% (Simard, Ward et al. 2012, American Cancer Society 2017). HCC is the fifth most common cancer in the world, and is the second leading cause of cancer mortality, responsible for between 250,000 and 800,000 deaths per year (Howlader N 2016). Most HCC patients are diagnosed at a late stage using conventional methods of detection, with a survival rate less than 5% after the diagnosis and subsequent treatment. The prognosis is much better if HCC patients are diagnosed at an early stage and treated with surgical and chemotherapeutic intervention. Unfortunately, the early stage of liver cancer is mostly asymptomatic, making the early detection of liver cancer a challenge.
Current methods in detecting HCC include monitoring high risk groups, such as those infected with HBV or HCV, with regular (usually annual or biannual) physical examinations, serum liver function tests (LFTs), ultrasound and other imaging studies. These methods all have their shortcomings. For example, ultrasound imaging is not sensitive for detecting small liver lesions. Other imaging methods, such as CT scan and MRI scan, are very expensive and submit patients to radiation exposure, prohibiting routine use of such methods.
In addition to imaging techniques, elevated serum concentrations of alpha-fetoprotein (AFP) is a useful surrogate marker for HCC, because on an average 50% of HCC patients have an elevated AFP level at the time of diagnosis. However, the elevated level of AFP is influenced by and can result from a number of non-malignant conditions. It is nearly impossible to detect HCC sufficiently early using current methods. Thus, there is a clear and urgent need for non-invasive, sensitive, reliable methods for the early detection of HCC (Bruix and Sherman 2011).
The high mortality rate of HCC (where 85% of patients die within 5 years) is mainly due to late detection and a high recurrence rate (Sherman 2008, Kamiyama, Nakanishi et al. 2009, Hung, Wong et al. 2016). Rates of recurrence range from 15% for liver transplantation to nearly 100% for surgery or ablation. Recurrence is most common within 2 years.
The high HCC recurrence rate can be attributed to (1) incomplete treatment, (2) micro-metastases within the liver, and (3) de novo lesions (Sherman 2008).
The early detection of recurrent HCC has been difficulty with the currently available diagnostic methods and serial imaging (Kamiyama, Nakanishi et al. 2009, Minami and Kudo 2015). Notably, there are no specific guidelines addressing how HCC recurrence should be monitored. MRI/CT imaging is the gold standard for diagnosis, although it is expensive and has limited utility in the detection of small tumors (<2 cm), tumors in the presence of previously treated lesions (especially from local ablation), cirrhosis, obesity, and dysplastic nodules (Willatt, Hussain et al. 2008, Minami, Nishida et al. 2014, Minami and Kudo 2015). Thus, there is an urgent unmet medical need to have a sensitive test for monitoring HCC recurrence.